Supersaturating oral delivery systems of poorly water-soluble compounds produced by hot melt extrusion

Ditzinger, Felix. Supersaturating oral delivery systems of poorly water-soluble compounds produced by hot melt extrusion. 2020, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_13624

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The field of enabling techniques for poorly water-soluble drugs has been growing over the last decades. Therefore, different formulation strategies and processes have gained relevance within the development of solid pharmaceutical dosage forms for oral drug delivery. A prominent example to manufacture such dosage forms is the process of hot melt extrusion, where mostly combinations of polymers and drugs are melted together and processed to result in an amorphous solid dispersion as a biopharmaceutically enhanced drug delivery system. The final extrudate needs to be further processed downstream for example in a mill or a pelletizer. Processing a drug in an extruded form comes with the advantage of increased apparent solubility and therefore increased amount of dissolved drug available for absorption in the gastrointestinal tract. A crucial quality attribute for this formulation approach is selecting the most suitable polymer in combination with a given drug. To identify the most suitable polymer, a variety of screening approaches can be applied. Some approaches make use of the Flory-Huggins interaction parameter or a comparison of Hansen solubility parameters, while an important experimental alternative is the screening of polymers for amorphous drug stabilization (SPADS) approach. However, a suitable polymer cannot always be found so that a compromise may lead to unbeneficial formulation characteristics. There is current research focusing on the development of new synthetic polymers based on chemical monomer engineering as well as the combination of polymers. Another approach is the addition of a small molecular additive for the stabilization of a drug without the necessary use of a polymer, i.e. so-called co-amorphous systems.
In this work, the interaction of an additive and the modification of the polymer are combined in molecularly designed polymeric matrices consisting of interacting small molecular additives and a polymeric excipient. The key aspect of this development is the specifically targeted molecular interaction between polymer and additive, which alters matrix characteristics thereby leading to possible benefits on the level of processing, amorphous stability and/or aqueous dispersion and drug release.
The first study consisted of establishing a concept of combining acidic co-formers with a basic polymer to improve processablity as well as drug release. In the beginning of this study, the co-former malic acid was identified to be most beneficial for the formulation with the polymer Eudragit E PO (dimethylaminoethyl methacrylate copolymer).
Interactions between the additive and the polymer were confirmed by Fourier transform infrared spectroscopy (FTIR) and 13C-nuclear magnetic resonance spectroscopy (NMR). These interactions were also present after the addition of the drug fenofibrate. In the next step, the amorphous stability of the additive-containing formulation was compared with the corresponding non-additive formulation via atomic force and scanning electron microscopy (SEM). By using energy dispersive X-ray spectroscopy during the SEM measurement, the drug was found to be dispersed homogenously in the malic acid formulation, whereas in the control formulation without additive, drug-rich domains were visible. This finding was supported by an observed phase separation in phasing images of atomic force microscopy using the control formulation.
In addition to the improved stability, the additive formulation showed improved drug release compared to the control formulation and the corresponding physical mixture. Since an extruded formulation requires further downstream processes, such as milling or grinding in a mortar, the powderized extrudate should have sufficient flowability to enable any subsequent processing such as tableting. The modified matrix formulation showed also in this technical aspect better flowability than the control formulation or the pure polymer.
To conclude in this case study on Eudragit E PO, the addition of malic acid to the polymer showed a specific molecular interaction and resulted in different formulation improvements with regards to amorphous stability, downstream processability as well as drug release.
In the second study, a polymer, which is not extrudable in its neat form, was modified in a way to make it applicable for extrusion. Different small molecular additives were investigated each as interacting partner with the polyelectrolyte sodium carboxymethyl cellulose (NaCMC). Studied additives were trometamol, urea, meglumine, and the amino acids lysine, histidine, arginine. These additives were intended to exert strong specific interactions with the macromolecular polyelectrolyte via acid-base-interactions. As manufacturing technique, a combination of solvent evaporation (with and without additive) and subsequent hot melt extrusion was conducted as a two-step process. Such processing served as a model of what an excipient supplier would do to make the modified NaCMC matrix available for a pharmaceutical company to process it together with a drug by hot melt extrusion. Initially, the maximum amount of additive in combination with NaCMC was determined for which an amorphous solid dispersion was still feasible as produced by extrusion. As a result, an excess molar amount of interacting additive was generally needed because amounts of additives below 15 % were shown not to be applicable for improving the extrusion behavior of the polymer. There was on the other hand also a maximum suitable additive concentration given with higher concentrations leading to residual crystallinity after extrusion.
The suitable polyelectrolyte matrices, which showed no indication of crystallinity in the laboratory X-ray diffraction analysis, were further investigated for homogeneity and crystallinity by synchrotron X-ray diffraction. Moreover, possible interactions and melting behavior were studied by hot stage microscopy and heat-assisted FTIR. It was shown that the polyelectrolyte matrices containing either meglumine, lysine, or urea resulted in an amorphous homogenous formulation. This finding was in line with the extrusion performance as well as the heat-assisted FTIR spectroscopy. Therefore, the promising meglumine and lysine excipient matrices were analyzed further in a subsequent study using a model drug.
In line with the assessment of glass forming ability, the third study was designed for the practical comparison of two crucial enabling techniques i.e. hot melt extrusion and mesoporous silica.
Therefore, two drugs, which are instable glass formers, were selected for a stability-based comparison under ICH Q1 accelerated stability conditions. For an increase in measurement sensitivity, the extruded samples were examined at the start of the study and the end using 13C solid-state NMR. This comparison was complemented by drug dissolution studies in biorelevant media at defined time points. In line with theoretical expectations about drugs that are challenging to stabilize in amorphous form, this study confirmed the superior stabilization capabilities of mesoporous silica formulations for which drug was successfully loaded and confined in mesopores. In contrast, the extruded formulations were not able to stabilize the challenging model drugs in their amorphous form over the duration of a three months stability study. These findings were underlined by results of the non-sink dissolution profiles at the defined time points, which showed a comparative decrease in supersaturation for the extruded formulations. The silica formulations, which were lacking the necessary precipitation inhibitor, showed just a “spring-effect” of high supersaturation but they could not sustain it without further excipients to act as a “parachute”. There was no decrease in the initial drug supersaturation visible over the duration of the study, which was in line with the solid-state evaluation. In conclusion, this study shows the advantage of mesoporous silica to formulate drugs that have a high tendency to recrystallize so that classical polymeric solid dispersions exhibit a substantial risk of physical instability.
The knowledge gained from the second study formed the basis of the fourth study. The two most promising candidates from the synchrotron study of the modified matrices, which were the lysine and the meglumine formulations, were further investigated regarding their biopharmaceutical properties. Thus, the model drug fenofibrate was selected as quantitative marker for in vitro and in vivo performance. During the pre-evaluation of the solid state, the amorphous form of both formulations was confirmed via powder X-ray diffraction as well as differential scanning calorimetry. Moreover, a possible interaction was investigated via FTIR.
The in vitro non-sink experiments in Fasted Simulated Intestinal Fluid (FaSSIF) showed a higher supersaturation and parachute effect for both formulations compared to the corresponding non-modified matrix without additive. The physical mixture only showed a slight drug release in the beginning, which decreased even more over time. Due to high viscosity, which was measured in separate rheological measurements, there was a 30 min delay in drug release observed in the extruded formulations. These findings agreed with results of the subsequent in vivo rat study, which showed a significant difference between the AUCs of the meglumine formulation and the corresponding physical mixture as well as differences in the Cmax values between both formulations and their physical mixtures. Therefore, this study showed the beneficial impact of the selected additives on the biopharmaceutical performance of the model drug fenofibrate.
In conclusion, this thesis focused on designing modified polymeric matrices based on targeted molecular interactions of additives and drug carriers. Small molecular additives were used in amorphous solid dispersions with a special emphasis on hot melt extrusion. It could be demonstrated that the careful selection of small molecular additives, which interact with a polymer, could have a beneficial impact on the manufacturing process, the physical stability, and/or biopharmaceutical release properties of a drug from its amorphous form. Different analytical methods supported the view of the intended molecular interactions in the modified matrices but the various technical and biopharmaceutical benefits are currently hard to predict theoretically. While we used molecular simulations occasionally to visualize candidate mixtures for experimental evaluation, a next step would be a more intensive use of in silico tools to predict formulation performance and to screen mixtures in the computer.
In line with current research and practice in the pharmaceutical industry, the selection of excipients during the early formulation development is crucial for the successful design of an amorphous drug delivery system on the market. This work showed that the addition of interacting small molecular additives could have a positive impact on the resulting matrix properties and therefore this would broaden the variety of suitable polymer matrices not by any covalent bonds in the synthesis of novel polymers but by virtue of a physical modification of the polymer through the given additive. The presented approach of a modified polymeric matrix therefore holds much promise in future pharmaceutical development of amorphous drug products.
Advisors:Imanidis, Georgios and Hamburger, Matthias
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Biologie (Hamburger)
UniBasel Contributors:Imanidis, Georgios and Hamburger, Matthias
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13624
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (ix, 142 Blätter)
Identification Number:
Last Modified:15 Sep 2020 01:30
Deposited On:06 Aug 2020 09:45

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